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Regorafenib is an orally available multikinase inhibitor, currently approved in metastatic chemorefractory colorectal cancer patients. The results of two large randomized Phase III trials are available, providing significant results in overall and progression-free survival in this situation. Its use requires a special attention regarding patient selection, dosing schedule and management of adverse events. Identifying patients who will tolerate and have benefit from regorafenib is a challenge for clinicians. Therapeutic monitoring (especially cfDNA), predictive biomarkers and specific perfusion-based imaging techniques will may be result in optimizing regorafenib treatment.

Over the past 20 years, management of patients with metastatic colorectal cancer (mCRC) has improved considerably, leading to increased overall survival and more patients eligible for third- or later-line therapy. Currently, two oral therapies are recommended in the third-line treatment of mCRC, regorafenib and trifluridine/tipiracil. Selecting the most appropriate treatment in the third-line setting poses different challenges compared with treatment selection at earlier stages. Therefore, it is important for physicians to understand and differentiate between available treatment options and to communicate the benefits and challenges of these to patients. In this narrative review, practical information on regorafenib is provided to aid physicians in their decision-making and patient communications in daily practice. We discuss the importance of appropriate patient selection and adverse events management through close patient monitoring and dose adjustments to ensure patients stay on treatment for longer and receive as much benefit as possible. We also highlight key physician–patient communication points to facilitate shared decision-making.

Background/Aim Presently, there are no therapeutic options for unresectable hepatocellular carcinoma (u‐HCC) patients who are intolerant to sorafenib or regorafenib failure. There have been no reports with detailed clinical findings of lenvatinib (LEN), a newly developed first‐line tyrosine kinase inhibitor (TKI), obtained in real‐world practice. We aimed to elucidate the therapeutic efficacy of LEN. Materials/Methods From March to August 2018, 105 u‐HCC patients were treated with LEN. Following exclusion of those who started with a reduced LEN dose and/or had a short observation period (<2 weeks), 77 patients (72.0 ± 8.9 years, 59 males, 8 mg/12 mg = 49/28, Liver Cancer Study Group of Japan 6th [LCSGJ]‐TNM stage II/III/IVa/IVb = 8/28/4/37, and American Joint Committee on Cancer/Union for International Cancer Control 8th [AJCC/UICC]‐TNM stage IB:II:IIIA:IIIB:IVA:IVB = 2:27:6:5:9:28) were divided into two groups (TKI naïve [n = 33] and TKI experienced [n = 44], including 11 with regorafenib history). Therapeutic response was evaluated using mRECIST. Clinical data were retrospectively evaluated. Results There were significant differences in age (74.6 ± 11.2 vs 70.0 ± 5.9 years, P = 0.040), LCSGJ‐TNM (II:III:IVa:IVb = 8:12:1:12 vs 0:16:3:25, P = 0.006), and AJCC/UICC‐TNM (IB:II:IIIA:IIIB:IVA:IVB = 2:17:1:1:4:8 vs 0:10:5:4:5:20, P = 0.028), while hepatic reserve function, adverse event (AE) profiles, and progression‐free survival (89.7%/80.4% vs 90.5%/80.1%, P = 0.499) and overall survival (96.7%/96.7% vs 100%/92.3%, P = 0.769) after 4 and 12 weeks were not significantly different between the TKI‐naïve and TKI‐experienced groups. Overall response rate and disease control rate at 4 weeks (n = 52) were 38.5% and 80.8%, respectively, and 32.4% and 70.3%, respectively, at 12 weeks (n = 37). A significant decline in log10 AFP from the baseline to 4 weeks after introducing LEN was observed in patients with PR and SD (2.047 ± 1.148 vs 1.796 ± 1.179, P < 0.001). Conclusion Regardless of past TKI therapy, therapeutic response and AEs after introducing LEN were similar. LEN may be an important treatment for the present unmet need regarding TKI treatment against u‐HCC. Presently, there are no therapeutic options for unresectable hepatocellular carcinoma (u‐HCC) patients who are intolerant to sorafenib or regorafenib failure, and there have been no reports with detailed clinical findings of lenvatinib (LEN), a newly developed first‐line tyrosine kinase inhibitor (TKI), obtained in real‐world practice. Regardless of past TKI therapy, therapeutic response and adverse events after introducing LEN were similar. LEN may be an important treatment for the present unmet need regarding TKI treatment for u‐HCC.

Objective To evaluate the efficacy and safety of regorafenib monotherapy or in combination with immune-checkpoint inhibitor while treating Chinese patients with metastatic colorectal cancer (mCRC): a real-world study. Methods The data of patients with metastatic colorectal cancer who received regorafenib-containing regimen as the third or later line treatment at ten Chinese hospitals from Aug 2017 to Jun 2020 were retrospectively analyzed, including dosing details, survival data as well as adverse events. Survival analysis was further performed for patients administrated with regorafenib monotherapy and combined with an immune-checkpoint inhibitor based on Kaplan-Meier and Cox regression methods. The primary endpoint was overall survival. Results A total of 537 patients were included with a median age of 61, among whom 376 received regorafenib monotherapy and 245 received regorafenib combined with immune-checkpoint inhibitors. The clinicopathological characteristics of the two groups at baseline were mainly balanced. No significant difference in progression-free survival (PFS) was observed in patients receiving regorafenib monotherapy or combination therapy (3.8 vs. 5.5 months, p  = 0.170). In contrast, patients receiving combination therapy had a more prolonged overall survival (OS) than those receiving regorafenib monotherapy (13.5 vs. 10.0 months, p  = 0.001). The treatment regimen and regorafenib dosage were significant prognostic factors in the multivariate analysis. Significant benefits in PFS and OS were achieved in KRAS mutant and anti-angiogenesis treatment-naïve subgroups receiving combination therapy compared to monotherapy. No apparent increase was recorded in treatment-related adverse events in patients receiving combination therapy. Conclusion Regorafenib plus an immune-checkpoint inhibitor has already been a widely adopted strategy in the later-line treatment for mCRC in the real world. The combination therapy yielded a significantly prolonged overall survival than regorafenib alone, with a manageable safety profile in Chinese patients, and warrants further investigation. Trial registration ClinicalTrials.gov Identifier: NCT04835324. Registered 6th April 2021.

Background Metastatic or recurrent bone sarcomas are often associated with an unfavorable prognosis, posing a formidable challenge in extending patients’ survival. Currently, regorafenib has shown promise in treating metastatic and recurrent bone sarcomas. However, there is a lack of consensus on its efficacy and safety. This systematic review and meta-analysis aims to consolidate existing data to assess the efficacy and safety of regorafenib in bone sarcomas. Methods A comprehensive search strategy utilizing MeSH terms and free-text keywords was employed to systematically search the Embase, PubMed, Web of Science, and Cochrane databases up to May 26, 2024. Randomized controlled trials investigating regorafenib monotherapy for metastatic or recurrent bone sarcomas were included. The primary outcomes of interest were progression-free survival (PFS), overall survival(OS) and adverse events (AEs). Results We retrieved 335 articles and included 5 of them. Regorafenib significantly extended PFS-3 months and PFS-6 months in patients with metastatic or recurrent bone sarcomas compared to the control group, exhibiting a favorable odds ratio (OR) of 2.04 (95% CI: 1.21–2.86, P  < 0.01) and 1.03 (95% CI: 0.08–1.99, P  < 0.05), respectively. However, regorafenib did not improve OS at any observation point compared with the control group( P  > 0.05), and the frequency of AEs was higher, with an odds ratio of 1.35 (95% CI: 0.63–2.07, P  < 0.01). Conclusion Regorafenib emerges as a promising therapeutic option for metastatic or recurrent bone sarcomas, demonstrating certain clinical benefits alongside manageable adverse reactions. Nevertheless, further research is warranted to refine the efficacy and safety profile of regorafenib, particularly in exploring safe dosage ranges or alternative treatment modalities. Registration number CRD42024551705.

Despite multimodal treatment with surgery and radiochemotherapy, the prognosis of glioblastoma remains poor, and practically all glioblastomas relapse. To date, no standard treatment exists for recurrent glioblastoma patients and traditional therapies have showed limited efficacy. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor showing encouraging benefits in recurrent GBM patients enrolled in the REGOMA trial. We performed a large study to investigate clinical outcomes and the safety of regorafenib in a real-life population of recurrent glioblastoma patients. Patients receiving regorafenib outside clinical trials at the Veneto Institute of Oncology were retrospectively reviewed. The major inclusion criteria were: histologically confirmed diagnosis of glioblastoma, prior first line therapy according to “Stupp protocol”, Eastern Cooperative Oncology Group (ECOG) performance status score ≤1. According to the original schedule, patients received regorafenib 160 mg once daily for the first 3 weeks of each 4-week cycle. The primary endpoints of the study were overall survival and safety. A total of 54 consecutive patients were enrolled. The median age was 56, MGMT methylated status was found in 28 out of 53 available patients (52.8%), IDH mutation in 5 (9.3%) and 22 patients were receiving steroids at baseline. The median overall survival was 10.2 months (95% CI, 6.4–13.9), the OS-12 was 43%. Age, MGMT methylation status and steroid use at baseline were not statistically significant on a multivariate analysis for OS. Patients reporting a disease control as best response to regorafenib demonstrated a significant longer survival (24.8 months vs. 6.2 months for patients with progressive disease, p = 0.0001). Grade 3 drug-related adverse events occurred in 10 patients (18%); 1 patient (2%) reported a grade 4 adverse event (rash maculo-papular). No death was considered to be drug-related. This study reported the first large “real-life” experience of regorafenib in recurrent glioblastoma. Overall, our results are close to the ones reported in the previous phase 2 study, despite the fact that we had a longer survival. We showed the encouraging activity and tolerability of this treatment in recurrent glioblastoma patients when used as a second-line treatment.

Purpose Previous randomized studies have shown a survival benefit of using regorafenib but a high rate of adverse events in unresectable colorectal cancer patients. To reduce these adverse events and improve the tolerability, we examined the appropriate dose of regorafenib based on body weight. Methods We used a nationwide claims database in Japan and examined the efficacy and safety of regorafenib for patients with metastatic colorectal cancer between groups divided by body weight (60 kg) and median average dose (120 mg) between 2013 and 2018. We also assessed overall survival (OS) and adverse events between these groups. Results We identified 2530 Japanese patients (heavy weight/high dose: 513, light weight/low dose: 921, heavy weight/low dose: 452, and light weight/high dose: 644). There was no significant difference in the adverse events and OS after inverse probability treatment weighting (IPTW) adjustment between heavy weight/high dose group and light weight/low dose group (hazard ratio, HR=0.97). Among the light-weight patients, higher average dose was associated with shorter OS (IPTW adjusted HR=1.21, 95% CI 1.05 – 1.39, Table 3 ) while among the heavy-weight patients, there was no significant difference in OS between high and low dose groups (IPTW adjusted HR=1.14, 95% CI 0.95 – 1.37). Conclusion The findings suggest that a low dose of regorafenib for light-weight patients may be as safe and effective as high doses for heavy-weight patients. Further studies should be conducted to identify an appropriate dose based on each patient's physique and condition.

Regorafenib is a multikinase inhibitor widely used in oncology, but it is associated with significant adverse events (AEs), particularly hepatotoxicity. Understanding the real-world safety profile and the molecular mechanisms underlying regorafenib-induced liver failure is critical for clinical risk management. AE reports with regorafenib as the primary suspect drug were extracted from the FDA Adverse Event Reporting System (FAERS) from Q3 2012 to Q1 2025. Disproportionality analyses were conducted using reporting odds ratio (ROR), proportional reporting ratio (PRR), multi-item gamma Poisson shrinker (MGPS), and Bayesian confidence propagation neural network (BCPNN). Clinical prioritization was assessed via a semi-quantitative framework. Time-to-onset was analyzed using Weibull distribution. Additionally, network toxicology and molecular docking were employed to explore potential mechanisms and binding affinities between regorafenib and liver failure targets. A total of 9,442 AE reports were analyzed. Hepatobiliary disorders exhibited the strongest signal strength (ROR = 2.66, 95% CI: 2.50-2.83), with hepatic failure and fulminant hepatitis identified as high-priority AEs. The majority of AEs occurred within 30 days of treatment initiation. Subgroup analysis indicated that elderly patients (≥65 years) and males had higher risks of liver failure, whereas higher body weight appeared protective. Network analysis identified 63 overlapping targets, with MAPK and PI3K-Akt signaling pathways significantly enriched. This pharmacovigilance analysis identifies regorafenib-associated hepatotoxicity as a significant safety signal, with higher risks observed in elderly and male patients. Computational predictions suggest the involvement of MAPK and PI3K-Akt pathways, offering a theoretical basis for further mechanistic investigation and supporting the need for vigilant clinical monitoring.

PurposeThe association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (Ctrough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer.MethodsThe Ctrough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5.ResultsWe analyzed 43 patients who received regorafenib 40–120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the Ctrough values of regorafenib were significantly higher in the group with grade ≥ 2 than in groups with grades 0 and 1 (p = 0.010). The M5 Ctrough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 Ctrough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035).ConclusionThis study showed that the Ctrough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the Ctrough of M5 was significantly correlated with hypertension and severe rash.

Colorectal cancer remains a leading cause of global cancer mortality, with metastatic CRC (mCRC) requiring sequential therapies after first line treatment failure. While regorafenib and fruquintinib are guideline-endorsed third-line options, their comparative value remains unestablished due to absent head-to-head trials. This real-world study evaluates clinical outcomes, safety, and cost differentials to model value-equilibrium pricing. A retrospective cohort analysis included 25 mCRC patients (regorafenib: n = 5; fruquintinib: n = 20) treated at Sichuan Cancer Hospital (2021-2022) with follow-up through June 2023. Outcomes included real-world disease control rate (rwDCR), adverse events (CTCAE v4.03-graded), and daily treatment costs (medication, dose adjustments, adverse event management). A Monte Carlo simulation modeled cost equilibrium using Generalized Beta Distribution-derived adverse event variability. Baseline characteristics were balanced (median age: 58-63; 60%-70% male). rwDCR showed no significant difference (20% vs 25%, p = 1.000). Regorafenib demonstrated higher grade 3-4 toxicities (60.0% vs 20.0%), including hepatotoxicity (40.0% vs 15.0%) and hand-foot skin reaction (20.0% vs 0%). Fruquintinib exhibited unique hypertension (10.0%) and proteinuria (20.0%). Regorafenib incurred 75% higher daily costs (¥455.53 vs ¥259.96, p = 0.001), primarily from medication expenses (¥439.82 vs ¥253.71, p = 0.014). Pharmacoeconomic modeling identified regorafenib's value-based pricing threshold at 47.35% of current costs (¥248.03/day; 95% CI: 247.98-248.09), revealing a 111% price-to-value mismatch. Fruquintinib demonstrates comparable efficacy with superior safety and cost-effectiveness in third-line mCRC. Regorafenib's pricing exceeds its clinical value by twofold, underscoring systemic misalignment between drug costs and therapeutic benefit. These findings advocate for value-driven pricing reforms integrating toxicity-related economic burdens and provide a replicable framework for indirect treatment comparisons in oncology. However, the small sample size reduced statistical power, potentially biasing the findings.